ARRA IMPACT REPORT:Epigenetics of Metabolic Disease

Public Health BurdenMetabolic diseases, such as diabetes mellitus, disrupt normal metabolism, the process of converting food to energy on a cellular level. Diabetes afflicts nearly 26 million people in the U.S. and another 79 million Americans are estimated to be at increased risk for developing the disease. Diabetes is the seventh leading cause of death in the U.S. and is a major cause of other deadly and costly diseases, including cardiovascular disease and kidney disease.

Advances in Understanding Effects of Maternal Diet on Epigenetics and Metabolic DiseaseEpigenetics is the study of differences in the way genes are expressed that are not caused by variations in DNA sequence. Epigenetic phenomena, such as DNA methylation, are thought to play an important role in the development of metabolic disease. For example, in a mouse model, mothers fed a diet rich in methyl compounds around conception gave birth to mice with increased DNA methylation and lower incidences of obesity and cancer. To advance the understanding of the epigenetic effects of maternal diet during human pregnancy, ARRA-funded investigators found the following:

Dietary Cadmium: Researchers at Harvard University determined that dietary cadmium was directly associated with first trimester methylation and inversely associated with cord blood methylation, suggesting it could be a potential determinant of DNA methylation and offspring health.1

Methylation and Preterm Birth: The Harvard investigators also examined associations of maternal and umbilical cord blood DNA methylation with length of gestation and odds of preterm birth to explore whether epigenetic mechanisms are involved in preterm birth. They found that DNA methylation in maternal blood during the first trimester was associated with longer gestations and decreased risk of preterm birth, whereas lower DNA methylation in cord blood was associated with preterm birth. Additional research is necessary to determine whether this DNA methylation is a potential biomarker for preterm birth or a risk factor.2

Advances Link Metabolic Disease, Epigenetics, and Circadian RhythmsMisaligning normal circadian rhythms, the biological “clocks” that harmonize the body with rhythmic changes in the environment, with behaviors such as sleep and eating (for example, working the night shift) increases vulnerability to diabetes, obesity, and other metabolic disorders. By studying a hormone receptor, called Rev-erb alpha, and discovering that it recruits an epigenetic factor, called HDAC3, ARRA-funded researchers have provided a critical link between circadian and metabolic physiology. These findings have made significant contributions to understanding how these processes are interrelated and potentially dysregulated in obesity and diabetes.

Circadian Rhythms and Metabolism: Investigators at the University of Pennsylvania found that fat metabolism in the liver is set to a circadian rhythm by the hormone receptor Rev-erb alpha, and an epigentic factor called HDAC3. By taking advantage of emerging technology (high-throughput next generation sequencing), researchers found that, in mice, certain genomic sites that are enriched for genes involved in lipid metabolism were bound by both HDAC3 and Rev-erb alpha during the day and therefore turned “off.” At night, when the mice were active and feeding, most of these sites were no longer associated with HDAC3 and Rev-erb alpha and were, therefore, turned “on,” promoting lipid synthesis. These findings demonstrated how circadian rhythms can significantly influence metabolism, and opened new possibilities in understanding obesity and diabetes and in developing targets for therapies.3

Hormone Receptors in Mouse Liver important link to Circadian Rhythm and Metabolism: The University of Pennsylvania investigators furthered understanding of the liver circadian clock by demonstrating that depleting both Rev-erb alpha and Rev-erb beta hormone receptors in mouse liver altered expression of several metabolic genes, as well as genes related to circadian rhythm. Genetically altering mice to lack both Rev-erbs resulted in marked fatty liver, highlighting the importance of these factors in the intersection of circadian rhythm and metabolism on health.4